Quinoline analogs as phosphatidylinositol 3-kinase inhibitors

ABSTRACT

The present disclosure provides selective phosphoinositide 3-kinase inhibitors of formula (A), or pharmaceutically acceptable salts thereof. These compounds are useful for the treatment of conditions mediated by one or more P13K isoforms, such as PI3K delta (PI3Kδ). The present disclosure further provides methods of inhibiting phosphoinositide 3-kinase inhibitors using these compounds for treatment of disorders related to phosphatidylinositol 3-kinase activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.16/072,150, filed Jul. 23, 2018 (now U.S. Pat. No. 10,795,283, issuedOct. 6, 2020), which is the U.S. national stage of International PatentApplication No. PCT/US2017/019970, filed Feb. 28, 2017, which claims thebenefit of priority of U.S. Provisional Patent Application No.62/304,148, filed on Mar. 4, 2016, the disclosures of which are herebyincorporated by reference in their entireties.

FIELD OF THE INVENTION

The present disclosure relates generally to quinoline analogs asinhibitors of phosphatidylinositol 3-kinase (PI3K) activity. Morespecifically, the invention further relates to the preparation of thedisclosed PI3K inhibitor analogs and their use in pharmaceuticalcompositions for the treatment of various diseases, conditions anddisorders related to PI3K activity.

BACKGROUND OF THE INVENTION

The class I phosphoinositide 3-kinases (P3Ks) regulatephosphatidylinositol 4,5-bisphosphate (PIP2) phosphorylation. PI3KConverts PIP2 to the scaffolding binding element phosphatidylinositol(3,4,5)-trisphosphate (PIP3). PIP3 plays a key regulatory role in cellsurvival, signal transduction, control of membrane trafficking and otherfunctions. (Di Paolo, G. et al. Nature 2006, 443, 651, Parker, P. J. etal. Biochem. Soc. Trans. 2004, 32, 893; Hawkins, P. T. et al. Biochem.Soc. Trans. 2006, 34, 647; Schaeffer, E. M. et al. Curr. Opin. Immnunol.2000, 12, 282). Its dysregulation leads to various disease states suchas cancer, inflammatory and auto-immune disorders.

The Class I PI3Ks consist of four kinases further delineated into 2subclasses. Class 1A PI3Ks consist of three closely related kinases,PI3Kα, β, and δ existing as heterodimers composed of a catalytic subunit(p110α, β or δ) and one of several regulatory subunits. They generallyrespond to signaling through receptor tyrosine kinases (RTKs). PI3Kγsingle class I B isoform, responds mainly to G-protein coupled receptors(GPCRs), and is composed of a p110γ catalytic subunit and one of twodistinct regulatory subunits. PI3Kα and PI3Kβ are ubiquitously expressedthroughout a wide variety of tissue and organ types. PI3Kγ is foundmainly in leukocytes, but also in skeletal muscle, livder, pancreas, andheart (Cantly, C. Science 2002, 1655). The expression pattern of PI3K isrestricted, to spleen, thymus, and peripheral blood leukocytes (Knight,Z. et al. Cell 2006, 125, 733).

PI3Kδ has been implicated as a major player in the adaptive immunesystem due to its expression pattern and evidence accumulated withgenetically modified mice. Recently, activated PI3K delta syndrome(APDS) was described, a primary immunodeficiencies (PD) associated witha dominant gain-of-function mutation in which lysine replaced glutamicacid at residue 1021 (E1021K) in the p110δ protein. APDS wascharacterized by recurrent respiratory infections, progressive airwaydamage, and lymphopenia (Ivan Angulo et al. Science 2013, 342, 866).PI3Kδ inhibitors can potentially be supplemental to the treatments ofB-cell related diseases such as rheumatoid arthritis (RA) and systemiclupus erythematosus (SLE) by the biologics rituximab (Rituxan) andbelimumab (Benlysta), as well as primary immunodeficiencies (PID).Several PI3Kδ selective inhibitors, such as, idelalisib (GS-1101),IPI-145 and AMG 319 have entered the clinic targeting hematologicalmalignancies, but few inhibitors have entered clinical trials foranti-inflammatory treatments (Cushing, T. et al. J Med Chem. 2015, 58,480).

In July 2014, the FDA and EMA granted first-in class PI3K deltainhibitor idelalisib approval to treat different types of leukemia; itssafety and effectiveness to treat relapsed FL and relapsed SLL wereestablished in a clinical trial with patients with indolent non-Hodgkinlymphomas. (“FDA approves Zydelig for three types of blood cancers”.Food and Drug Administration. Jul. 23, 2014). However, the U.S. labelfor idelalisib has a boxed warning describing toxicities that can beserious and fatal, including liver toxicity. Fatal and/or serioushepatotoxicity occurred in 18% of patients treated with idelalisibmonotherapy and 11% of patients treated with idelalisib in combinationtrials. Elevations in ALT or AST are greater than 5 times the upperlimit of what has occurred normally. The liver toxicity may be relatedto the inhibition and induction of CYP enzymes by idelalisib and itsmetabolite GS-563117.(http://www.accessdata.gov/drugsatfcla_docs/nda/2014/2065450rig1s000ClinP-harmR.pdf)

More recently, it was reported that p110δ inactivation in mice protectsagainst a broad range of cancers, including non-haematological solidtumors, and that p110δ inactivation in regulatory T cells unleashesCD8(+) cytotoxic T cells and induces tumor regression. Thus, p110δinhibitors can break tumor-induced immune tolerance and potentially havewide usage in oncology. (Ali, et al., Nature: 2014, 510, 407411). Therestill remains an unmet need for optimal PI3K delta inhibitors. Forexample, PI3K delta inhibitor can have improved in vivo stability toovercome the liability of inhibition or induction of CYP enzymes; anideal PI3K delta inhibitor can have the potential of combinationtreatment of malignant tumors with other anti-cancer interventions, suchas emerging immunotherapies. The present invention provides novelcompounds that are inhibitors of PI3K isoforms with significantlyimproved profiles.

SUMMARY

Compounds and pharmaceutically acceptable salts, prodrug, or solvatethereof useful for inhibiting PI3K isoforms, such as PI3K delta, aredescribed herein. Compositions, including pharmaceutical compositionsthat include the compounds are also provided, as are methods of usingand making the compounds. The compounds provided herein may find use intreating diseases, disorders, or conditions that are mediated by PI3Kisoforms, such as PI3K delta.

In one aspect, provided is a compound of formula (A), or apharmaceutically acceptable salt, prodrug, or solvate wherein:

X is N or CH;

Each R₁ and R₂ is independently H, F, or SO₂Me.

R₃ is F or Cl.

In one embodiment of formula (A) where X is N, both R₁ and R₂ are H, R₃is 7-F. The compound is of compound (2) in Table 1; or apharmaceutically acceptable salt, prodrug, or solvate thereof.

In another embodiment of formula (A) where X is C, R₁ is H, R₂ is2-SO₂Me, R₃ is 8-F, the compound is compound (7) in Table 1, or apharmaceutically acceptable salt, prodrug, or solvate thereof.

Also provided is a method of treating PI3K-mediated conditions ordisorders with a compound of formula (A), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof. Further provided is amethod of treatments of inflammatory diseases, such as asthma, chronicobstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis,and lupus.

Also provided is a method of inhibiting the growth or proliferation ofcancer cells comprising contacting the cancer cells with an effectiveamount of a compound of formula (A), or a pharmaceutically acceptablesalt, prodrug, or solvate. Also provided is a method for increasingsensitivity of cancer cells to chemotherapy, comprising administering toa patient undergoing chemotherapy with a chemotherapeutic agent and acompound of formula (A), or a pharmaceutically acceptable salt, prodrug,or solvate, sufficient to increase the sensitivity of cancer cells tothe chemotherapeutic agent.

Also provided are articles of manufacture that include a compound offormula (A), or a pharmaceutically acceptable, or prodrug, or solvatethereof.

DETAILED DESCRIPTION

It is intended and understood that each and every variation of R₁ and R₂may be combined with each and every variation of X as described forformula (A), as if each and every combination is individually described.

PI3K Inhibitor Compounds

Provided herein are compounds that function as PI3K inhibitors. In oneaspect, provided is a compound of formula (A), or a pharmaceuticallyacceptable salt, prodrug, or solvate wherein:

X is N or CH;

Each R₁ and R₂ are independently H, F, or SO₂Me.

R₃ is F or Cl.

In one embodiment of formula (A) where X is N, both R₁ and R₂ are H, R₃is 7-F. The compound is of compound (2) in Table 1; or apharmaceutically acceptable salt, prodrug, or solvate thereof.

In another embodiment of formula (A) where X is C, R₁ is H, R₂ is2-SO₂Me, R₃ is 8-F, the compound is compound (7) in Table 1, or apharmaceutically acceptable salt, prodrug, or solvate thereof.

TABLE 1 Representative Quinoline Compounds of Formula (A) # StructureName 1

2,4-Diamino-6- [1-(7-fluoro-2- phenyl- quinolin- 3-yl)- ethylamino]-pyrimidine-5- carbonitrile 2

2,4-Diamino-6- [1-(7-fluoro-2- pyridin-2-yl- quinolin-3-yl)-ethylamino]- pyrimidine-5- carbonitrile 3

2,4-Diamino-6- {1-[2-(3,5- difluoro- phenyl)- 7-fluoro- quinolin-3-yl]-ethylamino}- pyrimidine-5- carbonitrile 4

2,4-Diamino-6- {1-[7-fluoro-2- (2- methane- sulfonyl- phenyl)-quinolin-3-yl]- ethylamino}- pyrimidine-5- carbonitrile 5

2,4-Diamino-6- {1-[7-fluoro-2- (3-fluoro- phenyl)- quinolin-3-yl]-ethylamino}- pyrimidine-5- carbonitrile 6

2,4-Diamino-6- [1-(8-fluoro-2- pyridin-2-yl- quinolin-3-yl)-ethylamino]- pyrimidine-5- carbonitrile 7

2,4-Diamino-6- {1-[8-fluoro-2- (2- methane- sulfonyl- phenyl)-quinolin-3-yl]- ethylamino}- pyrimidine-5- carbonitrile 8

2,4-Diamino-6- [1-(8-chloro-2- pyridin-2-yl- quinolin-3-yl)-ethylamino]- pyrimidine-5- carbonitrile

Provided are also compounds of formula (A), or pharmaceuticallyacceptable salts, prodrugs, or solvates thereof. In certain embodiments,provided herein are also crystalline and amorphous forms of thecompounds of formula (A), or pharmaceutically acceptable salt prodrugs,or solvents thereof.

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids (Berge et al., J. Pharm. Sci. 1977, 66-1).

A“solvate” is formed by treating a compound in a solvent. Solvates ofsalts of the compounds of formula (A) are also provided. In the case oftreating compounds with water, the solvate is hydrates. Hydrates of thecompounds of formula (A) are also provided.

A “prodrug” includes any compound that converts into a compound offormula (A), when administered to a subject, e.g., upon metabolicprocessing of the prodrug.

Therapeutic Uses of the Compounds

The compounds of formula (A), or pharmaceutically acceptable salt,prodrug, or solvate thereof may be used for treating PI3K mediateddiseases or disorders. In one embodiment, provided are methods forinhibiting PI3K delta activity using a compound of formula (A), or apharmaceutically acceptable salt, prodrug, or solvate thereof. Inanother embodiment. PI3K delta and gamma isomers may both be inhibitedto achieve optimal efficacy.

In addition to the therapeutic uses described herein, selected compoundsof formula (A), or a pharmaceutically acceptable salt, prodrug, orsolvate thereof, have improved properties in at least one of thefollowing parameters: (i) human hepatocyte stability, and (ii)pharmacokinetic profiles (PK) including oral exposure.

In another embodiment, selected compounds of formula (A), or apharmaceutically acceptable salt, prodrug, or solvate thereof haveimproved human hepatocyte stability. Human hepatocyte stability in manycases correlates with pharmacokinetics in human better than thecorresponding rodent pharmacokinetic studies. According to someembodiments, selected compounds may have hepatocyte stability of ahalf-life of greater than 24 hours.

As used herein, “treat” or “treating” in reference to a disorder meansto ameliorate or prevent the disorder or one or more of the biologicalmanifestations of the disorder, to interfere with one or more points inthe biological cascade that leads to or is responsible for the disorder,to alleviate one or more of the symptoms or effects associated with thedisorder. As indicated above, “treatment” of a disorder includesprevention of the disorder, and “prevention” is understood to refer tothe prophylactic administration of a drug to substantially diminish thelikelihood or severity of a disorder or biological manifestationthereof, or to delay the onset of such disorder or biologicalmanifestation thereof.

“Subject” refers to a human (including adults and children) or otheranimal. In one embodiment, “patient” refers to a human.

As used herein, “safe and effective dose” in reference to a compound offormula (A), or a pharmaceutically acceptable salt, prodrug, or solvatethereof an amount sufficient to treat the patient's condition but lowenough to avoid serious side effects. A safe and effective dose of acompound will vary with the particular compound chosen (e.g. considerthe potency, efficacy, and half-life of the compound); the route ofadministration chosen; the disorder being treated; the severity of thedisorder being treated; the age, size, weight, and physical condition ofthe patient being treated; the medical history of the patient to betreated; the duration of the treatment; the nature of concurrenttherapy: the desired therapeutic effect; and like factors.

“Inhibition of PI3K delta activity” or variants refer to a decrease inPI3K delta activity as a direct or indirect response to the presence ofa compound of formula (A), or a pharmaceutically acceptable salt,prodrug, or solvate thereof, relative to the activity of PI3K delta inthe absence of the compound of formula (A), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof.

The term “PI3K delta selective inhibitor” generally refers to a compoundthat inhibits the activity of the PI3K delta isoform more effectivelythan other isoforms of the PI3K family (e.g., PI3K alpha, beta, orgamma).

The potencies of compounds as inhibitors of an enzyme activity (or otherbiological activity) can be established by determining theconcentrations at which each compound inhibits the activity to apredefined extent and then comparing the results. “IC50” or “IC90” of aninhibitor can be determined by the concentration that inhibits 50% or90% of the activity in a biochemical assay, which can be accomplishedusing conventional techniques known in the art, including the techniquesdescribes in the Examples below.

PI3K delta is expressed primarily in hematopoietic cells includingleukocytes such as T-cells, dendritic cells, neutrophils, mast cells,B-cells, and macrophages. Due to its integral role in immune systemfunction. PI3K delta is also involved in a number of diseases related toundesirable immune response such as allergic reactions, inflammatorydiseases, inflammation mediated angiogenesis, rheumatoid arthritis,auto-immune diseases such as lupus, asthma, emphysema and otherrespiratory diseases. By inhibiting aberrant proliferation ofhematopoietic cells, PI3K delta inhibitors can ameliorate the symptomsand secondary conditions that result from a primary effect such asexcessive system or localized levels of leukocytes or lymphocytes.

In one aspect, the invention thus provides a method of treating adisorder mediated by inappropriate PI3-kinase activity comprisingadministering a safe and effective dose of a compound of formula (A), ora pharmaceutically acceptable salt, prodrug, or solvate thereof.

In one embodiment, PI3K mediated diseases or disorders are selected fromthe group consisting of respiratory diseases (including asthma, chronicobstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis(IPF)); allergic diseases (including allergic rhinitis and atopicdermatitis); autoimmune diseases (including rheumatoid arthritis andmultiple sclerosis); inflammatory disorders (including inflammatorybowel disease); hematologic malignancies; solid tumors;neurodegenerative diseases; pancreatitis; kidney diseases;transplantation rejection; graft rejection; lung injuries

In one embodiment, the compounds described herein may be used to treatcancers that are mediated by inappropriate PI3K delta activity. Incertain embodiments, the disease is a hematologic malignancy. In certainembodiments, the disease is lymphoma, such as Burkitt lymphoma, diffuselarge B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), follicularlymphoma, lymphoplasmacytic lymphoma. Waldenstrom macroglobulinemia andmarginal zone lymphoma. In one embodiment, the disorder is multiplemyeloma, or leukemia, such as acute lymphocytic leukemia (ALL), acutemyeloid leukemia (AML), chronic lymphocytic leukemia (CLL), smalllymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS),myeloproliferative disease (MPD), chronic myeloid leukemia (CML).

In other embodiments, the disease is a solid tumor. In particularembodiments, the indication is to treat solid tumor with abnormal PI3Kdelta expression, such as pancreatic cancer, gastric cancer, esophagealcancer, and breast cancer. In some embodiment, the compounds alone orwith combination of other anti-cancer therapies may be used to treatprostate cancer, bladder cancer, colorectal cancer, renal cancer,hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer,head and neck cancer, melanoma, neuroendocrine cancers, brain tumors,bone cancer, or soft tissue sarcoma.

In some embodiments, PI3K mediated diseases or disorders are severeautoimmune disease as asthma, type I diabetes, rheumatoid arthritis,multiple sclerosis, chronic obstructive pulmonary disease (COPD), andlupus.

Combination Therapies

In one embodiment, a compound of formula (A), or a pharmaceuticallyacceptable salt, prodrug, or solvate may be used in combination with oneor more additional therapeutic agents to treat cancers or inflammatorydisorders. The one or more additional therapeutic agents may be achemotherapeutic agent, a radiotherapy, a targeted therapy, animmunotherapeutic agent or any current best of care treatment, either asa small molecule or a biologic nature.

Targeted therapies include but not limit to an inhibitor tocyclin-dependent kinase (CDK) such as CDK1, CDK2, CDK4/6, CDK7, andCDK9, Janus kinase (JAK) such as JAK1, JAK2 and/or JAK3, spleen tyrosinekinase (SYK), Bruton's tyrosine kinase (BTK), mitogen-activated proteinkinase (MEK) such as MEK 1 and MEK2, bromodomain containing proteininhibitor (BRD) such as BRD4, isocitrate dehydrogenase (IDH) such asIDH1, histone deacetylase (HDAC), or any combination thereof.

Chemotherapeutic agents may be categorized by their mechanism of actioninto: alkylating agents, antimetabolites, anti-microtubule agents,topoisomerase inhibitors and cytotoxic agents. A compound of formula(A), or a pharmaceutically acceptable salt, prodrug, or solvate may beused in combination with chemotherapeutics to sensitize and improve theefficacy of certain chemotherapeutic agents to treat blood or solidtumors.

The immunotherapeutic agents include and are not limited to therapeuticantibodies, small molecules and vaccines suitable for treating patients;such as IDO1 and TDO2 inhibitors, A2A receptor inhibitors, arginaseinhibitors, toll-like receptor agonists, chemokine regulators (includingCCR and CXCR families), check point blockage antibodies such asantibodies that regulate PD-1, PD-L1, CTLA-4, OX40-OX40 ligand, LAGS,TIM3, or any combination thereof.

Radiotherapy is part of cancer treatment to control or kill malignantcells and commonly applied to the cancerous tumor because of its abilityto control cell growth. A compound of formula (A), or a pharmaceuticallyacceptable salt, prodrug, or solvate may be used in combination withradiotherapy, to improve the efficacy of radiotherapy to treat blood orsolid tumors, or with surgery, chemotherapy, immunotherapy andcombination of the four.

In certain embodiments, a compound of formula (A), or a pharmaceuticallyacceptable salt, prodrug, or solvate may be used in combination with oneor more additional therapeutic agents to treat patients who aresubstantially refractory to at least one chemotherapy treatment, or inrelapse after treatment with chemotherapy.

Pharmaceutical Compositions

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (A), or a pharmaceuticallyacceptable salt, prodrug, or solvate salt thereof and a pharmaceuticallyacceptable carrier or excipient. The pharmaceutical composition can beformulated for particular routes of administration such as oraladministration, parenteral administration, and topical administration,etc.

Compositions intended for oral use are prepared according to any methodknown in the art for the manufacture of pharmaceutical compositions andcan be prepared in the form of tablets, pills, powders, suspensions,emulsions, solutions, syrups, and capsules. Oral composition may containthe active ingredient in admixture with nontoxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.The tablets are uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. Formulations for oraluse can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application. e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orspray formulations. e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurized container, pump, spray, atomizer ornebulizer, with or without the use of a suitable propellant.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

Modes of Administration and Dosing

The pharmaceutical compositions may be administered in either single ormultiple doses. A compound of formula (A), or a pharmaceuticallyacceptable salt, prodrug, or solvate salt thereof can be formulated soas to provide the desired release schedule of the active ingredientbased on the therapeutic treatment purpose.

The pharmaceutical composition is preferably made in the form of adosage unit containing a particular amount of the active ingredient inthe form of tablets, pills, powders, suspensions, emulsions, solutions,syrups, and capsules. For example, these may contain an amount of activeingredient from about 0.1 to 1000 mg, preferably from about 0.1 to 500mg. A suitable daily dose for a human or other mammal may vary widelydepending on the condition of the patient and other factors, but, onceagain, can be determined using routine methods. The daily dose can beadministered in one to four doses per day. For therapeutic purposes, theactive compounds of this invention are ordinarily combined with one ormore adjuvants appropriate to the indicated route of administrationdrops suitable for administration to the eye, ear, or nose. A suitabletopical dose of active ingredient of a compound of the invention is 0.1mg to 150 mg administered one to four, preferably one or two timesdaily. For topical administration, the active ingredient may comprisefrom 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation,preferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

In a particular embodiment, the method comprises administering to thesubject an initial daily dose of about 0.1 to 500 mg of a compound offormula (A) and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg canbe used to increase the dose. The dosage can be increased daily, everyother day, twice per week, or once per week.

Synthesis of the Compounds of Formula (A)

The compounds of formula (A) may be prepared using the methods disclosedherein and routine modifications thereof, which will be apparent giventhe disclosure herein and methods are well known in the art.Conventional and well-known synthetic methods may be used in addition tothe teachings herein. The synthesis of representative compoundsdescribed herein may be accomplished as described in the followingexamples. If available, reagents may be purchased commercially, e.g.,from Sigma Aldrich or other chemical suppliers.

General

Reagents and solvents used below can be obtained from commercialsources. 1H-NMR spectra were recorded on a Mercury 300 MHZ NMRspectrometer. Significant peaks are tabulated in the order: multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz (HZ) and number ofprotons. Mass spectrometry results are reported as the ratio of massover charge, followed by the relative abundance of each ion (inparentheses Electrospray ionization (ESI) mass spectrometry analysis wasconducted on an Agilent 1100 series LC/MSD electrospray massspectrometer. All compounds could be analyzed in the positive ESI modeusing acetonitrile water with 0.1% TFA as the delivery solvent.

Synthetic Reaction

The terms “solvent”, “inert organic solvent”, or “inert solvent” referto a solvent inert under the conditions of the reaction being describedin conjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, dichloromethane (DCM), diethyl ether, methanol, pyridine andthe like. Unless specified to the contrary, the solvents used in thereactions of the present invention are inert organic solvents, and thereactions are carried out under an inert gas, preferably nitrogen.

Preparation of 8-Substituted Quinoline Amines

Example 1: (S)-1-(8-Fluoro-2-pyridin-2-yl-quinolin-3-yl)-ethylamine (9)

Step 1:

To a solution of 2-chloro-8-fluoroquinoline-3-carboxaldehyde (1.5 g, 7.2mmol) in anhydrous THF (20 mL) was added titanium isopropoxide (4.3 mL,1.4 mmol) at r.t. After 15 minutes, (R)-2-methyl-2-propanesulfinamide(0.867 g, 7.2 mmol) was added and stirring was continued overnight atr.t. Water (100 mL) was added to the reaction mixture and theprecipitate obtained was filtered and washed with DCM. The organic layerwas dried (Na₂SO₄), filtered and concentrated in vacuo to give the crudematerial as a pale yellow solid which was purified by columnchromatography on silica gel (EtOAc/hexane, 4/5)) to give a pale yellowsolid (2.0 g, 89%). Mass Spectrum (ESI) m/e: 313 (M+1).

Step 2:

To a solution of 2-Methyl-propane-2-sulfinic acid2-chloro-8-fluoro-quinolin-3-ylmethyleneamide (0.95 g, 2.8 mmol) in DCM(22 mL) was added dropwise MeMgCl (1.94 mL, 5.8 mmol; 3 M in THF) over10 minutes at −78° C. under nitrogen. The reaction mixture was allowedto reach r.t. with stirring overnight. The mixture was cooled inice-salt as saturated aqueous NH4Cl (50 mL) was slowly added withstirring. The aqueous layer was extracted with DCM (2-50 mL). Theorganic layer was dried (MgSO4) filtered and concentrated in vacuo togive a yellow oil which was purified by column chromatography on silicagel (EtOAc/hexane, 4/5 to EtOAc) to give a pale yellow solid (26 mg,28%). Mass Spectrum (ESI) m/e: 329 (M+1).

Step 3:

A mixture of (S)-2-Methyl-propane-2-sulfinic acid[1-(2-chloro-8-fluoro-quinolin-3-yl)-ethyl]-amide (0.186 g, 0.57 mmol),Pd(PPh3)4 (0.066 g, 0.057 mmol. 0.1 eq) and 2-(tributylstannyl)-pyridine(0.51 g, 1.4 mmol, 2.4 eq) in dioxane (5 mL) was heated to 110° C. underN2. After stirring overnight, the combined solvents were concentratedand purified by column chromatography on silica gel (EtOAc) to give2-Methyl-propane-2-sulfinic acid1-(8-fluoro-2-pyridin-2-yl-quinolin-3-yl)-ethyl-amide (160 mg, 43%).Mass Spectrum (EST) m/e: 372 (M+1).

To a solution of the above material (160 mg) in MeOH (2 mL) was added 4N HCl in dioxane (2 mL) at rt and the resulted reaction mixture wasstirred for 2 hours and concentrated under reduced pressure. Ethyl etherwas added and sonicated for 2 min and filtered to give(S)-1-(8-fluoro-2-pyridin-2-yl-quinolin-3-yl)-ethylamine as HCl salt.Mass Spectrum (ESI) m/e: 268 (M+1).

(S)-1-(8-Chloro-2-pyridin-2-yl-quinolin-3-yl)-ethylamine (10) and(S)-1-[8-Fluoro-2-(2-methanesulfonyl-phenyl)-quinolin-3-yl]-ethylamine(11) were prepared in the similar manner.

Preparation of 7-Substituted Quinoline Amines

Example 2: (S)-1-(7-Fluoro-2-phenyl-quinolin-3-yl)-ethylamine (12)

Compound(S)-2-(1-(2-Chloro-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione wasprepared according to the literature (J. Med. Chem. 2015, 58, 480-511).This compound (280 mg, 0.79 mmol), phenylboronic acid (146 mg, 1.2mmol), and potassium carbonate (328 mg, 2.4 mmol) were combined in 6 mLof anhydrous DMF under an atmosphere of N2. The solution was purged withN2 for .about. 5 min before adding PdCl2(dppf)DCM (64 mg. 0.079 mmol).The solution was heated at 100° C. for 3 h, and then cooled to 50° C.The solution was concentrated under vacuum to give a brownish residue,which was diluted with EtOAc (12 mL). The organic layers were thenwashed with water (3×3 mL), followed by brine (10 mL). The combined aq.layers were extracted with DCM (3×2 mL). The combined organic layerswere dried over MgSO4 and then concentrated under vacuum. The residueobtained was purified by silica gel flash chromatography eluting with agradient of 20% to 40% EtOAc/hexane. The fractions containing the pureproduct were combined and concentrated under vacuum to give(S)-2-[1-(7-fluoro-2-phenyl-quinolin-3-yl)-ethyl]-isoindole-1,3-dione(263 mg, 84% yield) as a light yellow foam. Mass Spectrum (ESI) m/e: 397(M+1).

To a slurried suspension of(S)-2-[1-(7-fluoro-2-phenyl-quinolin-3-yl)-ethyl]-isoindole-1,3-dione(260 mg, 0.65 mmol) in anhydrous ethanol (3 mL) was added NH2NH2 (0.11g, 5.0 eq) dropwise. The reaction mixture was heated to 90° C. for 30min and cooled to rt. The reaction mixture was filtered and washed withEtOAc. The resulting EtOAc solution was washed with water, brine anddried over Na2SO4. Removal of solvents gave a tan oil of(S)-1-(7-fluoro-2-phenyl-quinolin-3-yl)-ethylamine (122 mg, 71%). MassSpectrum (ESI) m/e: 267 (M+1).

(S)-1-[2-(3,5-Difluoro-phenyl)-7-fluoro-quinolin-3-yl]-ethylamine (14),(S)-1-[7-Fluoro-2-(2-methanesulfonyl-phenyl)-quinolin-3-yl]-ethylam-ime(15), and (S)-1-[7-Fluoro-2-(3-fluoro-phenyl)-quinolin-3-yl]-ethylamine(16) were prepared in the similar manner.

Example 3: (S)-1-(7-fluoro-2-(pyridin-2-yl) quinolin-3-yl)ethanamine(13)

A mixtureof(S)-2-(1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione(0.86 g, 2.4 mmol), Pd(PPh3)4 (0.28 g, 0.24 mmol, 0.1 eq) and2-(tributylstannyl)-pyridine (1.07 g, 2.9 mmol, 1.2 eq) in dioxane (30mL) was heated to 90° C. under N2. After stirring overnight. LC-MSshowed 30% completion. The reaction mixture was heated to 101° C. foradditional 2 days. The reaction mixture was then cooled to rt and theresulted solid was filtered and washed with EtOAc to give a tan solid of2-((S)-1-(7-fluoro-2(pyridin-2-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dio-newas obtained (0.84 g, 88%). Mass Spectrum (ESI) m/e: 398 (M+1).

To a slurried suspension of2-((S)-1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)isoindoline-1,3-di-one(0.84 g, 2.1 mmol) in anhydrous ethanol (5 mL) was added NH2NH2 (0.34 g,10.4 mmol) dropwise. The reaction mixture was heated to 90° C. for 30min and cooled to rt. The reaction mixture was filtered and washed withEtOAc. The resulting EtOAc solution was washed with water, brine anddried over Na2SO4. Removal of solvents gave a tan oil of(S)-1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine (399 mg, 71%).Mass Spectrum (ESI) m/e: 268 (M+1).

Preparation of 2,4,6-Triamino-pyrimidine-5-carbonitrile

Ammonium hydroxide (4 mL) was added to a solution of2,4,6-trichloropyrimidine-5-carbonitrile (1.0 g, 4.8 mmol) in dioxane (4mL) at room temperature. The solution was warned to 50° C. and stirredfor 3 hrs. The reaction mixture was cooled to 10° C. and water (10 mL)was added. The resulting solid was filtered, washed with water, anddried under high vacuum to afford 2,4,6-triamino-pyrimidine-5carbonitrile as a white solid (0.8 g). Mass Spectrum (ESI) ne: 170(M+H).

Preparation of(S)-2,4-diamino-6-{1-[7-fluoro-2-(3-fluoro-phenyl)-quinolin-3-yl]-ethylamino}-pyrimidine-5-carbonitrile(5)

Potassium fluoride (34 mg, 0.58 mmol) was added to a solution of(S)-1-[7-fluoro-2-(3-fluoro-phenyl)-quinolin-3-yl]-ethylamine (90 mg,0.31 mmol) and 2,4-diamino-6-chloropyrimidine-5-carbonitrile (60 mg,0.35 mmol) in diisopropylethylamine (0.1 mL, 0.60 mmol) and DMSO (2 mL).The resultant mixture was heated to 100° C. for 14 hours, after whichtime the reaction was cooled to room temperature, and diluted with water(5 mL) and the resulted solid was filtered, washed with water and driedand purified by preparative TLC to give a white solid as(S)-2,4-diamino-6-{1-[7-fluoro-2-(3-fluoro-phenyl)-quinolin-3-yl]-ethylam-ino}-pyrimidine-5-carbonitrile.Mass Spectrum (ESI) m/e: 418 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.49(s, 1H), 8.10 (dd, J=5.7, 3.0 Hz, 1H), 7.75 (dd, J=11, 2.4 Hz, 1H),7.52-7.60 (m, 3H), 7.27-7.32 (m, 1H), 7.12 (d. J=7.2 Hz, 1H), 6.52 (s,2H), 6.10 (s, br, 2H), 5.40-5.45 (m, 1H), 1.30 (d, J=6.9 Hz, 3H).

The following compounds were prepared in the similar manner.

(S)-2,4-diamino-6-[1-(7-fluoro-2-phenyl-quinolin-3-yl)-ethylamino]-pyrimidine-5-carbonitrile(Compound 1, Table 1). Mass Spectrum (ESI) m/e: 400 (M+1). 1H NMR (300MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 8.07 (dd, J=6.6, 2.4 Hz, 1H),7.67-7.70 (m, 2H), 7.49-7.52 (m, 3H), 7.13 (d, J=7.5 Hz, 1H), 6.52 (s,2H), 6.10 (s, br, 2H), 5.45-5.50 (m, 1H), 1.27 (d, J=6.9 Hz, 3H).

(S)-2,4-Diamino-6-[1-(7-fluoro-2-pyridin-2-yl-quinolin-3-yl)-ethyla-mino]-pyrimidine-5-carbonitrile(Compound 2, Table 1). Mass Spectrum (ESI) m/e: 401 (M+1). 1H NMR (300MHz. DMSO-d6) δ ppm 8.72 (s, 1H), 8.56 (m, 1H), 7.54-8.12 (m, 6H), 6.50(s, 2H), 6.08 (s, br, 2H), 5.65-5.75 (m, 1H), 1.35 (d, J=6.9 Hz, 3H).

(S)-2,4-Diamino-6-{1-[2-(3,5-difluoro-phenyl)-7-fluoro-quinolin-3-y-l]-ethylamino}-pyrimidine-5-carbonitrile(Compound 3, Table 1). Mass Spectrum (ESI) m/e: 436 (M+1). 1H NMR (300MHz, DMSO-d6) δ ppm 8.52 (s, 1H), 8.13 (dd, J=5.7, 3.0 Hz, 1H), 7.76(dd, J=7.5.1.8 Hz, H), 7.54-7.60 (m, 1H), 7.08-7.45 (m, 2H), 7.09 (d,J=6.9 Hz, 1H) 6.52 (s, 2H), 6.12 (s, br, 2H), 5.35-5.40 (m, 1H), 1.34(d, J=6.3 Hz, 3H).

(S)-2,4-Diamino-6-{1-[7-fluoro-2-(2-methanesulfonyl-phenyl)-quinoli-n-3-yl]-ethylamino}-pyrimidine-5-carbonitrile(Compound 4, Table 1). Mass Spectrum (ESI) m/e: 478 (M+1). 1H NMR (300MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 8.13 (dd, J=5.7, 3.0 Hz, 1H) 7.77-7.89(m, 4H), 7.56-7.61 (m, 1H) 7.06 (d, J=7.5 Hz, 1H), 6.54 (s, 2H), 6.24(s, br, 2H), 5.15-5.25 (m, 1H), 3.37 (s, 3H), 1.27 (d, J=6.9 Hz, 3H).

(S)-2,4-Diamino-6-[1-(8-fluoro-2-pyridin-2-yl-quinolin-3-yl)-ethyla-mino]-pyrimidine-5-carbonitrile(Compound 6, Table 1). Mass Spectrum (ESI) m/e: 401 (M+1). 1H NMR (300MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 8.16 (m, 1H), 7.54-8.02 (m, 6H), 6.51(s, 2H), 6.01 (s, br, 2H), 5.23-5.34 (m, 1H), 1.30 (d. J=6.9 Hz, 3H).

(S)-2,4-Diamino-6-{1-[8-fluoro-2-(2-methanesulfonyl-phenyl)-quinoli-n-3-yl]-ethylamino}-pyrimidine-5-carbonitrile(Compound 7, Table 1). Mass Spectrum (ESI) m/e: 478 (M+1). 1H NMR (300MHz, MeOH-d4) δ ppm 8.74 (d, J=4.5 Hz, 1H), 8.51 (s, 1H), 8.03-7.94 (m,2H), 7.80 (d, J=8.4 Hz, 1H), 7.61-7.45 (m, 4H), 5.84 (q, J=6.9 Hz, 1H),4.60 (s, 1H), 3.33 (s. 3H), 1.41 (d, J=6.9 Hz, 3H).

(S)-2,4-Diamino-6-[1-(8-chloro-2-pyridin-2-yl-quinolin-3-yl)-ethyla-mino]-pyrimidine-5-carbonitrile(Compound 8, Table 1). Mass Spectrum (ESI) m/e: 417 (M+1). 1H NMR (300MHz, DMSO-d6) δ ppm 8.74 (d. J=4.5 Hz, 1H), 8.60 (s, 1H), 8.06-7.94 (m,3H), 7.75 (d, J=8.4 Hz, 1H), 7.64-7.53 (m, 2H), 6.48 (s, 2H), 5.80-5.74(m. 1H), 1.39 (d, J=6.0 Hz, 3H).

Biological Examples

Activity testing was conducted in the Examples below using methodsdescribed herein and those well known in the art.

Characterization of Compounds of Formula (A)

This Example compares the biological activity and hepatocyte stabilityof the compounds of formula (A) to 4-amino-2-hydrogen pyrimidine analogsD-F such as compounds having the following structure (Compounds D-F werereported in patent US2013/0267524 and compound D is a close analog forreference purpose).

Enzymatic activity of different PI3K isoforms was measured to comparethe PI3K isoform selectivity of the tested compounds, particularlyselectivity of PI3K delta. Hepatocyte stability was also measured toassess the potential half-life of the tested compounds in humansubjects.

Each of these biological experiments are described below.

Enzymatic Activity of PI3K Isoforms

Enzymatic activity of the class I PI3K isoforms in the presence of thecompounds of Table 1 above was measured using a time-resolvedfluorescence resonance energy transfer (TR-FRET) assay.

The TR-FRET assay can monitor formation of the product 3,4,5-inositoltriphosphate molecule (PIP3) as it competed with fluorescently labeledPIP3 for binding to the GRP-1 pleckstrin homology domain protein. Anincrease in phosphatidylinositide 3-phosphate product results in adecrease in TR-FRET signal as the labeled fluorophore is displaced fromthe GRP-1 protein binding site.

The PI3K isoforms were assayed under initial rate conditions in thepresence of 10 μM ATP, and compounds were tested in 10-dose IC50 modestarting at a concentration of 0.5 μM. Control compound, PI-103, wastested in 10-dose IC50 with 3-fold serial dilution starting at 10 μM.

Data are normalized based on negative (DMSO) control. The alpha, beta,delta, and gamma IC50 values were calculated from the fit of thedose-response curves to a four parameter equation. IC50 are reported inunits of nM.

IC50 values were obtained for all PI3K isoforms (α, β, δ, and γ), andTable 2 summarizes the IC50 data collected for PI3Kδ in this Example.

Hepatocyte Stability

The hepatocyte assay was used to evaluate the metabolic stability oftest articles (TA) following incubation in cryopreserved hepatocytes bymonitoring parent drug disappearance via LC/MC. The TA with 1% finalDMSO concentration was incubated with 0.5 million hepatocytes/ml at 1 μMsubstrate in duplicate. The incubation was carried out at 37° C. with 5%CO₂ and saturating humidity. Samples were taken at 0, 1, 2, and 3 hoursto monitor the disappearance of TA and a half-life (t ½) was determined.Table 2 below summarizes the t½ values (e.g. t ½) collected from thisExample.

TABLE 2 Compound IC₅₀ (nM) hepatocyte T_(1/2) (h) 1  0.043 27 2  0.08653 3 0.24 17 4 0.27 6 5 0.14 20 6 — 9 7 2.1  59 8 0.97 — D — 10 E — 4.8H — 0.88 G — 1.2 F — 5.9

The results from this example demonstrate that compounds 1 and 4 offormula (A) have moderately improved stability in human hepatocytes(i.e. longer half-life), than compounds D and E (2.7× and 1.3×).However, several compounds showed surprisingly dramatic improvement forthe stability in human hepatocytes (i.e. longer half-life); Table 3below shows the comparison of t h of Compounds 2, 5, 7, H, G, and F. Thedramatically improved stability of compounds in human hepatocytes willlikely reduce the formation of drug metabolites in vivo and maycontribute positively to the safety of the compounds in the clinicaltrials.

TABLE 3 Compounds 2 5 7

T ½ (h) >48 >12 >48 Compounds H G F

T ½ (h) <1 <1.5 <6

Compound 2 was dosed by both iv and PO in the rats. Shown in Table 4 isa comparison of PK profiles of 2 and marketed PI3K delta inhibitoridelalisib, also known as CAL-101 (PK data from idelalisib NDA filing):Compound 2 showed remarkably increased oral exposure after oral dose (10mg/kg) in the SD rats. Oral exposure corrected with dose (AUCinf/dose)is 20 fold higher than that of idelalisib.

TABLE 4 AUC_(inf) AUC_(inf/)/ C_(max) C_(max/) T_(max) t_(1/2) V_(SS) ClTest article (hr*ng/mL) Dose (ng/mL) Dose (hr) (hr) (L/kg) (ml/min/kg) F% CAL-101 (IV) 1151 ± 407 384 ± 136 1437 ± 220 479 ± 73 0.06 1.89 2.49478 ± 19 NA CAL-101 (oral) 422 ± 67 141 ± 22  129 ± 49  43 ± 16 3.001.52 NA NA 39 ± 13 Comp 2 (iv) 4552 3448 1093 828 0.08 3.55 1.12 4.6Comp 2 (po) 29491 2949 3173 317 2 3.12 NA NA 80Cytotoxicity assay of compound 2 of Table 1 in selected cell lines

Procedure

Day 0: cell seeding for all cell lines with the density of 10000cells/80 μL/well.

Day 1, drug treatment: Prepare 3-fold serial dilutions of compound stocksolutions with growth medium. Dispense 20 μL (5×) drμg solution in eachwell (duplicates for each concentration), the final DMSO concentrationof each well treated with test compound and corresponding vehiclecontrol is 0.1%. Incubate the plate for 72 h in specified incubator.

Day 4, plate reading: Thaw CTG solution and equilibrate to roomtemperature, add 100 μL of CTG per well, mix the contents for 2 min onthe plate shaker, incubate for 10 min before recording the luminescencesignal using Envision.

Data Analysis

The Cell viability (percent of control=T/C, the optical density of thetest well after a 3-day period of exposure to test drug is T, and thecontrol optical density is C) of each dose were fitted using a nonlinearregression model with a sigmoidal dose response with GraphPad Prismversion 5, and the IC50 that the concentration of test drug where100×T/C=50 were calculated

TABLE 5 IC50 (μM) SU-DHL- SU-DHL- SU-DHL- Compound EHEB JVM-2 4 5 6Compound 2 0.216 0.931 0.088 0.493 0.035 Idelalisib 0.506 1.426 0.1981.683 0.130 Cisplatin 2.592 0.749 0.507 0.280 5.606

1-20. (canceled)
 21. A compound having a structure of formula (A), or apharmaceutically acceptable salt, or solvate thereof:

wherein X is selected from the group consisting of N or CH; each R₁ andR₂ is independently selected from the group consisting of H, F, andSO₂Me, and R₃ is F.
 22. The compound of claim 21, wherein R₃ is 7-F or8-F.
 23. The compound of claim 22, wherein X is N, and each of R₁ and R₂is H.
 24. The compound of claim 22, wherein X is CH and R₁ is SO₂Me. 25.The compound of claim 22, wherein X is CH and R₁ is F.
 26. The compoundof claim 22, wherein X is CH, R₁ is H and R₂ is H.
 27. The compound ofclaim 21, wherein the compound is


28. The compound of claim 21, wherein X is CH, R₁ is H, R₂ is 2-SO₂Me,and R₃ is 8-F.
 29. The compound of claim 21, wherein the compound'shepatocyte stability ranges from 6 to 59 T_(1/2) (h), and wherein thecompound has improved pharmacokinetics (PK) data than known PI3Kδinhibitors.
 30. A pharmaceutical composition comprising the compound ofclaim 21, or a pharmaceutically acceptable salt, or solvate thereof, andone or more of a pharmaceutically acceptable carrier and/or excipient.31. A method of treating a phosphoinositide 3-kinase delta (PI3Kδ)mediated disease or disorder, comprising administering to a subject inneed thereof a therapeutically effective amount of the compound of claim21, or a pharmaceutically acceptable salt or solvate thereof.
 32. Themethod of claim 31, wherein the PI3Kδ mediated disease or disorder isselected from the group consisting of cancer, respiratory diseases,allergic diseases, autoimmune diseases, inflammatory disorders,neurodegenerative diseases, pancreatitis, kidney diseases,transplantation rejection, graft rejection, and lung injuries.
 33. Themethod of claim 31, wherein the PI3Kδ mediated disease or disorder is ahematologic malignancy or solid tumor.
 34. The method of claim 33,wherein the PI3Kδ mediated disease or disorder is a hematologicmalignancy and the hematologic malignancy is a lymphoma, multiplemyeloma, or leukemia.
 35. The method of claim 34, wherein the lymphomais Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), follicular lymphoma, lymphoplasmacytic lymphoma,Waldenstrom macroglobulinemia, small lymphocytic lymphoma (SLL), ormarginal zone lymphoma; and the leukemia is acute lymphocytic leukemia(ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL),myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), orchronic myeloid leukemia (CML).
 36. The method of claim 33, wherein thesolid tumor is associated with pancreatic cancer, gastric cancer,esophageal cancer, and breast cancer.
 37. The method of claim 36,wherein the compound is


38. A method of treating cancer or an inflammatory disorder, comprisingadministering to a subject in need thereof the compound of claim 21, ora pharmaceutically acceptable salt or solvate thereof, and one or moreadditional therapeutic agents to treat cancers or inflammatorydisorders.
 39. The method of claim 38, wherein the inflammatory diseaseis asthma, chronic obstructive pulmonary disease, rheumatoid arthritis,multiple sclerosis, inflammatory bowel disease, or lupus.
 40. The methodof claim 38, wherein the cancer is pancreatic cancer, gastric cancer,esophageal cancer, breast cancer, prostate cancer, bladder cancer,colorectal cancer, renal cancer, hepatocellular cancer, lung cancer,ovarian cancer, cervical cancer, head and neck cancer, melanoma,neuroendocrine cancers, brain tumors, bone cancer, or soft tissuesarcoma.